Formulations providing three distinct releases

ABSTRACT

A therapeutic preparation consisting of three groups of spheroids containing an active medicinal substance. The first group of spheroids is uncoated and rapidly disintegrates upon ingestion to release an initial dose of medicinal substance a second group of spheroids is coated with a pH sensitive coat to provide a second dose and a third group of spheroids is coated with a pH independent coat to provide a third dose. A powder blend of active medicinal substance may be substituted for the first group of uncoated spheroids. The therapeutic preparation may be utilized as a mixture of groups of spheroids in a capsule.

This is a division of application Ser. No. 100,646, filed Sept. 24, 1987U.S. Pat. No. 4,794,001 which in turn is a divisional of Ser. No.836,033 filed Mar. 4, 1986 and now U. S. Pat. No. 4,728,512 which inturn is a continuation-in-part of application Ser. No. 731,175, filedMay 6, 1985 now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to pharmaceutical preparations for oraladministration encapsulated in a capsule dosage form and moreparticularly relates to such therapeutic preparations comprising coatedpellets or spheroids which release a dose of an active medicinalsubstance at different times in the digestive system of a patient.

Timed disintegration capsules for the sequential, timed release ofmedicinal substances into a patient's system are known in the art.Generally such capsules or tablets consist of particles containing themedicinal substance to be introduced into the system, and a coating overthe particles of a material which is resistant to disintegration for aselected period of time. Such coating compositions are also referred toas enteric coating compositions, that is, compositions which aregenerally resistant to disintegration in the stomach, but whichdisintegrate in the intestine. Enteric compositions also includecompositions which disintegrate slowly in the stomach such that themedicinal substance is not released until the capsule or tablet hasreached the intestine of the patient. For example, coatings comprisingbees wax and glyceryl monostearate; bees wax, shellac and cellulose; andcetyl alcohol, mastic and shellac have been proposed for use as slowrelease or timed release coatings for medicinal substances. Release ofthe medicinal substance by disintegration of the coating is generallycontrolled by varying the thickness of the coating or by altering itscomposition.

U.S. Pat. No. 2,809,918 discloses inert drug coated nonpareils which areenteric coated with a shellac-stearic acid mixture. U.S. Pat. No.3,119,742 discloses coated drug crystals used as particulates forsustained release formulations. U.S. Pat. No. 2,921,883 discloses"Spansule," nonenteric coated spheroids designed for sustained release.U.S. Pat. No. 3,835,221 discloses oral delayed action "globules" coatedwith a mixture of polyvinylacetate and ethyl cellulose, useful as an"inert carrier core." F. W. Goodhart et al., Pharmaceutical Technology,page 64-71, Apr. 1984, discloses the evaluation of Eudragit E 30 D as anaqueous film forming dispersion for controlled release ofphenylpropanolamine hydrochloride.

The prior art compositions have generally proved deficient in the casewhere the medicinal substance is extensively metabolized presystemicallyor has a relatively short elimination half-life resulting insub-therapeutic plasma levels. Also, with many patients, the coatingsare not disintegrated to the extent necessary to release the medicinalsubstance until the tablet or capsule has reached the colon and themedicinal substance is discharged from the system rather than absorbedby the intestine.

The present invention provided three repeated releases of a medicinalsubstance for once daily administration of those medicinal substanceswhich are extensively metabolized presystemically or have relativelyshort elimination half-lives. This system results in superior oralbioavailability as compared to a continuous release system for amedicinal substance over a 6 to 24 hour period. The present inventionalso provides the convenience of not requiring the administration ofdivided doses during a 24 hour period and results in better patientcompliance.

The medicinal agents useful in the invention are those that exhibit asignificant presystemic metabolism or have a relatively shortelimination half life that normally would be administered in divideddosess two or more times a day. Such medicinal agents include thecardiovascular drugs such as propanolol hydrochloride, isosorbidedinitrate, isosorbide-5-mononitrate, pelrinone (see U.S. Pat. No.4,505,910), acifran (see U.S. Pat. No. 4,244,958) verapamilhydrochloride, quinidine sulfate, the cerebral activators such asvinpocetine, Ay-30109 (see U.S. Pat. application Ser. No. 811,551, filedDec. 20, 1985 by Jirkovsky et al., entitled 6, 7, 8,9-Tetrahydro-10-methylpyrido[1,2-a]indole-9-Amines and DerivativesThereof (AHP-8728); the analgesics such as those disclosed and claimedin U.S. Pat. application Ser. No. 726,197, filed Apr. 22, 1985, theantihistamines such as chlorpheniramine and bromopheniramine; and thedecongestants such as pseudoephedrine and phenylpropanolamine.

In the case of medicinal agents having a significant pH dependentsolubility profile, weak organic acids such as citric, tartaric, fumaricand glutamic acids may be added to the spheroid formulation tofacilitate drug dissolution throughout the gastrointestinal tract.

The present invention also lies in the general area of timeddisintegration coatings and represents a substantial improvement overthe prior art compositions in that the time of disintegration is readilycontrollable and easily adjusted for release of a medicinal substance.

The present invention relates to a therapeutic composition comprising apharmaceutical gelatin capsule containing (i) a powder blend of amedicinal substance and two groups of spheroids each containing themedicinal substance or (ii) three groups of spheroids each containing amedicinal substance, the alternative group of spheroids comprisinguncoated spheroids containing a loading dose of the medicinal substance.In each embodiment, the second group of spheroids comprises pH sensitivecoated spheroids containing a second dose of the medicinal substnce andthe third group of spheroids comprises double coated spheroidscontaining a third dose of the medicinal substance.

A further preferred aspect of the present invention relates to atherapeutic composition consisting of a pharmaceutical gelatin capsulecontaining three groups of spheroids wherein, (a) the first group ofspheroids comprises an active medicinal substance admixed with non-waterswellable microcrystalline cellulose, (b) the second group of spheroidscomprises the medicinal substance in admisture with non-water swellablemicrocrystalline cellulose and is coated with a copolymer based onmethacrylic acid and methacrylic acid methyl ester such as Eudragit S tothe extent of 20% to 30% by weight of uncoated spheriods or polyvinylacetate phthalate to the extent of 5% to 15% by weight of uncoatedspheroids and preferably to the extent of 10% by weight and (c) thethird group of spheroids comprises the medicinal substance in admixturewith non-water swellable microcrystalline cellulose and is coated with(i) an undercoat to the extent of 2.5% to 5.5% by weight of uncoatedspheroids selected from the group consisting of hydroxypropylmethylcellulose and hydroxypropyl methylcellulose containing as adisintegrant sodium carboxymethylcellulose, such as AcDiSol, or sodiumstarch glycolate such as Explotab, werein the AcDiSol is present to theextent of 10% to 60% by weight of the hydroxypropyl methylcellulose andthe Explotab is present to the extent of 10% to 60% by weight of thehydroxypropyl methyl celulose and an (i) overcoat comprising a neutralcopolymer of polymethacrylic acid esters such as Eudragit E30Dcontaining metallic stearates wherein the Eudragit E30D is present tothe extent of 5% to 12% by weight of the uncoated spheroids and themetallic stearate is present to the extent of 9% to 16% by weight of theEudragit E30D solids and preferably about 12.5% by weight of theEudragit E30D solids.

A separate and distinct aspect of the present invention relates to thedouble coated spheroids used as the third dose of the active medicinalsubstance.

Suitable pharmaceutical excipients for the powder blend of the medicinalsubstance include lactose, microcrystalline celulose, starch, calciumphosphate, calcium sulfate, stearic acid, magnesium stearate anddisintegrants.

Eudragit S is a copolymer, anionic in character, based on methacrylicacid and methacrylic acid methyl ester. The ratio of free carboxylicgroups to the esters is approximately 1:2. The mean molecular weight is135,000. Eudragit S is available as a lacquer solution in isopropylalcohol and as a solvent free solid. It is known as methacrylic acidcopolymer, Type B, N.F.

Eudragit E30D is a copolymer, neutral in character, based onpolymethacrylic acid esters. The mean molecular weight is 800,000.Eudragit E 30 D is available as a 30% (28.5%-31.5%) aqueous dispersion.Both Eudragit S and Eudragit E30D are available from Rohm Pharma, D-6108Weiterstadt 1, Dr. -Otto -Rohm-Str. 2-4, West Germany.

Metalic stearates include zinc stearate, calcium stearate and magnesiumstearate.

Explotab is a trade name for sodium starch glycolate. Sodium starchglycolate is the sodium salt of a carboxymethyl ether of starch. It isavailable from Edward Mendell Co., Inc., Route 52, Carmel N.Y. 10512,U.S.A.

AcDiSol is a trade name for carboxymethylcellulose sodium. It is thesodium salt of a polycarboxymethyl ether of cellulose, available fromFMC Corporation, 200 Market St., Philadelphia, Pa. 19103, U.S.A.

Other disintegrants such as Amberlite can be used instead of Explotaband AcDiSol.

Suitable grades of hydroxypropyl methylcellulose for use in the presentinvention are the Methocel brand, made by Dow Chemical Comany, Midland,Mich., U.S.A., grades E, F and K having a viscosity range of about 3500to about 5600 cps and preferably a viscosity of about 4000 cps.

Also suitable grades of hydroxypropyl methylcellulose are the Metolosebrand, made by Shin-Etsu Chemical Co., Ltd., grades 60 SH, 65 SH and 90SH having a viscosity range of about 3500 to about 5600 cps andpreferably a viscosity of about 4000 cps.

Methocel F is a grade of hydroxypropyl methylcellulose containing about27 to 30% methoxyl content and from about 4.0 to 7.5% hydroxypropoxylcontent calculated on the dried basis. Methocel K is a grade ofhydroxypropyl methylcellulose containing about 19 to 25% methoxylcontent and from about 4 to 12% hydroxypropoxyl content calculated onthe dried basis.

The preferred grade of hydroxypropyl methylcellulose for use in thepresent invention is hydroxypropyl methylcellulose USP, 2910, 4000 cps(METHOCEL E4AMP) which is a propylene glycol ether of methylcellulosecontaining not less than 28.0% and not more than 30.0% methoxyl content,and not less than 7.0% and not more than 12.0% hydroxypropoxyl content.

A suitable non-water swellable microcrystalline cellulose is, forexample, the material sold as Avicel-PH-101 (available from FMCCorporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.,U.S.A.).

The polyvinyl acetate phthalate, available from Colorcon, Inc., is thestandard grade.

The spheroid coatings may further contain other pharmaceuticallyacceptable excipients such as binders, fillers, anti-adherents and thelike.

A still further preferred aspect of the present invention relates to atherapeutic composition comprising a pharmaceutical hard gelatin capsulecontaining three groups of spheroids containing an active medicinalsubstance, wherein (a) the first group of spheroids comprising uncoatedspheroids contains the medicinal substance for maximum release thereofwithin a period of two hours after ingestion, (b) the second group ofspheroids comprising coated spheroids contains the medicinal substancein a spheroid core coated with a pH sensitive coat comprising acopolymer based on methacrylic acid and methacrylic acid methyl ester orpolyvinyl acetate phthalate, the coat having an effective thickness toprovide a maximum release of medicinal substance in a period of 2 to 6hours after ingestion, and (c) the third group of spheroids comprisingcoated spheroids contains medicinal substance in a spheroid core coatedwith an undercoat of hydroxypropyl methylcellulose and an overcoat of aneutral copolymer based on polymethacrylic acid esters containingmetallic stearates, the coats having an effective thickness to provide amaximum release of medicinal substance 4 to 10 hours after ingestion.

The following examples are by way of illustration of the preferredembodiments of the therapeutic preparation of the present invention andits manner of preparation.

In the first four of these examples, the uncoated spheroids were made inaccordance with the teachings of U.S. Pat. No. 4,138,475 in thefollowing manner:

Propanolol hydrochloride (60 kg.) and microcrystalline cellulose(Avicel-PH-101; 40 kg.) were blended together in a 450 liter planetarymixer. Water (50 kg.) was added, and the mixer was run for 10 minutesuntil a homogeneous, plastic mass was obtained. The mass was extrudedunder pressure through a perforated cylinder to give cylindricalextrudates of nominally 1 mm. diameter.

The damp extrudates (in batches of 15 to 20 kg.) were placed in aspheronizer in which the rotating disc (diameter 68 cm.) rotated at 300to 400 r.p.m. The rotation was continued for 10 minutes, and theresulting spheroids were then dried at 60° C. in a fluidized bed drier.The dried spheroids were passed over a 1.4 mm. screen, and those whichpassed through were subjected to a 0.7 mm. screen. The over-andunder-sized spheroids were discarded.

EXAMPLE 1

The finished dosage form consists of a hard gelatin capsule containing apowder blend of propanolol hydrochloride and two types of spheroids. Theformulation particulars are based on 160 mg propanolol hydrochloride percapsule, although they can be designed to provide other dosagestrengths.

The propranolol hydrochloride powder blend (or first group of spheroids)provides the loading dose, (e.g. 25 mg propanolol HCl).

The second and third types of spheroids are categorized as:

(1) pH sensitive coated spheroids to provide a second dose (pH 6.5) e.g.65 mg propranolol HCl.

(2) Coated spheroids to provide a third dose (4-10 hours post ingestion)e.g. 70 mg propranolol HCl.

    ______________________________________                                                           Quantity                                                   ______________________________________                                        1.   Powder Blend                                                                  (a) Formula                                                              Ingredient                                                                    Propranolol HCl, USP 30       mg/capsule                                      Lactose, USP         54       mg/capsule                                      Microcrystalline cellulose, NF                                                                     15       mg/capsule                                      Magnesium stearate, NF                                                                             1        mg/capsule                                      2.   pH Sensitive Coated Spheroids                                            (i)  Eudragit S System:                                                            (a) Formula (based on 3 kg uncoated spheroids)                           Ingredients                                                                   Uncoated Spheroids (60%                                                                            3.00     kg                                              w/w Propranolol HCl)                                                          Methacrylic Acid Copolymer,                                                                        0.75     kg                                              Type B, NF                                                                    Eudragit S                                                                    Triacetin, USP       0.112    kg                                              Methylene Chloride, NF                                                                             1.99     kg                                              Isopropyl Alcohol, USP                                                                             1.64     kg                                              Water                0.50     kg                                              (b) Process                                                                   Uncoated spheroids were placed in a fluidized bed coater                      The Eudragit S solution was applied using a peristaltic                       pump                                                                          The spheroids were dried                                                      3.   Coated Spheroids                                                              (a) Formula (based on 3 kg uncoated spheroids)                           Undercoat Ingredients                                                         Uncoated Spheroids (60%                                                                            3.00     kg                                              w/w propranolol HCl)                                                          Hydroxypropyl methylcellulose,                                                                     0.075    kg                                              USP, 2910, 4000 cps, (e.g.,                                                   Methocel E4MP)                                                                Methylene Chloride, NF                                                                             4.987    kg                                              Methanol, Anhydrous, NF                                                                            2.963    kg                                              Overcoat Ingredients                                                          Eudragit E 30 D (Aqueous                                                                           1.00     kg                                              Dispersion)                                                                   Calcium Stearate, NF 0.030    kg                                              Simethicone Emulsion, USP                                                                          0.0025   kg                                              Water, USP, Purified 0.500    kg                                              (b) Process for applying undercoat                                            The uncoated spheroids were placed in a fluidized bed coater                  Methocel E4MP solution was sprayed using a peristaltic pump                   The spheroids were dried                                                      (c) Process for applying overcoat                                             Eudragit E 30 D suspension containing calcium stearate was                    sprayed on the Methocel E4MP coated spheroids using a                         peristaltic pump                                                              The spheroids were dried                                                      4.   Manufacture                                                                   Capsules were filled with the powder blend, pH-sensitive                      coated spheroids and coated spheroids on an encapsulating                     machine capable of dual filling powders and spheroids.                   ______________________________________                                    

EXAMPLE 2

The finished dosage form consists of a hard gelatin capsule containing 3types of spheroids. The formulation particulars are based on 160 mgpropranolol HCl per capsule, although they can be designed to provideother dosage strengths.

The three types of spheroids are categorized as:

(1) Uncoated spheroids to provide a loading dose (e.g. 30 mg propranololHCl)

(2) pH sensitive coated spheroids to provide a second dose (pH 5.5) e.g.60 mg propranolol HCl

(3) Coated spheroids to provide a third dose (4-10 hours post ingestion)e.g. 70 mg propranolol HCl

    ______________________________________                                                              Quantity                                                ______________________________________                                        1.  Uncoated Spheroids (prepared as described previously)                     2.  Alternate pH Sensitive Coated Spheroids                                       Polyvinyl Acetate Phthalate (PVAP) system:                                    (a) Formula - (based on 3 kg uncoated spheroids)                          Ingredients                                                                   Uncoated Spheroids (60% 3.00 kg                                               w/w propranolol HCl)                                                          Polyvinyl Acetate Phthalate (PVAP), NF                                                                0.30 kg                                               Triethyl Citrate, NF    0.03 kg                                               Stearic Acid, NF        0.06 kg                                               Methanol, Anhydrous, NF 2.61 kg                                               (b) Process                                                                   Uncoated spheroids were placed in a fluidized bed coater                      The PVAP solution was applied using a peristaltic pump                        The spheroids were dried                                                      3.  Coated Spheroids (prepared as described above in Example                  ______________________________________                                            1)                                                                    

EXAMPLE 3

    ______________________________________                                                             Quantity/Batch                                           ______________________________________                                        1.  Uncoated Spheroids (prepared as described above)                          2.  pH Sensitive Coated Spheroids (prepared as described above in                 Example 1                                                                 3.  Coated Spheroids                                                              (a) Formula (based on 3 kg uncoated spheroids)                            Undercoat Ingredients                                                         Uncoated Spheroids (60%                                                                              3.0     kg                                             w/w propranolol HCl)                                                          Hydroxypropyl methylcellulose, USP,                                                                  0.075   kg                                             2910, 4000 cps (Methocel E4MP)                                                Methylene Chloride, NF 4.987   kg                                             Methanol, Anhydrous, NF                                                                              2.963   kg                                             Overcoat Ingredients                                                          Eudragit E 30 D (aqueous dispersion)                                                                 0.600   kg                                             Calcium Stearate, NF   0.0225  kg                                             Simethicone Emulsion USP                                                                             0.002   kg                                             Water, USP, Purified   0.300   kg                                             (b) Process for applying undercoat                                            The uncoated spheroids were placed in a fluidized bed coater                  Methocel E4MP solution was applied using a peristaltic pump                   The spheroids were dried                                                      (c) Process for applying overcoat                                             Eudragit E 30 D suspension containing calcium stearate was                    sprayed on the Methocel E4MP coated spheroids using a                         peristaltic pump                                                              The spheroids were dried                                                      The three types of spheroids are categorized as:                              (1) Uncoated spheroids to provide a loading dose (e.g. 30 mg                  propranolol HCl)                                                              (2) pH sensitive coated spheroids to provide a second dose (pH 6.5)           e.g. 60 mg propranolol HCl                                                    (3) Coated spheroids to provide a third dose (4-10 hours post ingestion)      e.g. 70 mg propranolol HCl                                                    ______________________________________                                    

EXAMPLE 4

    ______________________________________                                                             Quantity/Batch                                           ______________________________________                                        1.  Uncoated Spheroids (prepared as described above)                          2.  pH Sensitive Coated Spheroids (prepared as described above in                 Example 1)                                                                3.  Coated Spheroids                                                              (a) Formula                                                               Undercoat Ingredients                                                         Uncoated Spheroids (60%                                                                              3.00    kg                                             w/w Propranolol HCl)                                                          Hydroxypropyl methylcellulose,                                                                       0.075   kg                                             USP, 2910, 4000 cps (E4MP)                                                    Methylene Chloride, NF 4.987   kg                                             Methanol, Anhydrous, NF                                                                              2.963   kg                                             Overcoat Ingredients                                                          Eudragit E 30 D (Aqueous Dispersion)                                                                 0.550   kg                                             Calcium Stearate, NF   0.021   kg                                             Simethicone Emulsion, USP                                                                            0.002   kg                                             Water, USP, Purified   0.275   kg                                             (b) Process for applying undercoat                                            The uncoated spheroids were placed in a fluidized bed coater                  Methocel E4MP solution was applied using a peristaltic pump                   The spheroids were dried                                                      (c) Process for applying overcoat                                             Eudragit E 30 D suspension containing calcium stearate was                    sprayed on the Methocel E4MP coated spheroids using a                         peristaltic pump                                                              The spheroids were dried                                                      The three types of spheroids are categorized as:                              (1) Uncoated spheroids to provide a loading dose (e.g. 30 mg                  propranolol HCl)                                                              (2) pH sensitive coated spheroids to provide a second dose (pH 6.5)           e.g. 60 mg propranolol HCl                                                    (3) Coated spheroids to provide a third dose (4-10 hours post ingestion)      e.g. 70 mg propranolol HCl                                                    ______________________________________                                    

The finished dosage form consists of a hard gelatin capsule containingthree types of spheroids containing propranolol hydrochloride. Theformulation particulars are based on 160 mg propranolol hydrochlorideper capsule, although they can be designed to provide other dosagestrengths as follows:

    ______________________________________                                                  First group                                                         Propranolol                                                                             of spheroids                                                                              Second group                                                                              Third group                                 Hydrochloride                                                                           (or powder) of spheroids                                                                              of spheroids                                mg per capsule                                                                          % of dose   % of dose   % of dose                                   ______________________________________                                        40 to 240 10% to 30%  20% to 75%  10% to 60%                                  160       12% to 20%  35% to 45%  35% to 45%                                  ______________________________________                                    

Examples of in vitro release profiles are given in FIG. 1-4. FIG. 1represents the dissolution profile of the composite capsule formulationcomprised of three separate doses, produced in Example 3. Thedissolution profile was obtained using the Unites States PharmacopeiaApparatus I at 37° C. and 100 RPM. The disssolution media was variedwith time beginning with 0.1N HCl for 0 to 2 hours. From 2 to 4 hoursthe media was pH 6.5 phosphate buffer and from 4 to 24 hours the mediawas pH 7.5 phosphate buffer.

FIG. 2 representsthe dissolution profiles of the first dose uncoatedspheroids produced in Examples 2, 3 and 4 vs the powder blend of thefirst dose in Example 1. The dissolution profiles were obtained usingthe United States Pharmacopeia Apparatus I at 37° C. and 100 RPM. Thedissolution media was 0.1N HCl.

FIG. 3 represents the dissolution profile of the second dose Eudragit Scoated spheroid produced in Example 1, 2, 3 and 4. The dissolutionprofile was obtained using the United States Pharmaceopeia Apparatus Iat 37° C. and 100 RPM. The dissolution media was varied with timebeginning with 0.1N HCl from 0 to 2 hours. From 2 to 4 hours the mediawas pH 6.5 phosphate buffer and from 4 to 24 hours the media was pH 7.5phosphate buffer.

FIG. 4 represents the dissolution profile of the third dose produced inExample 3. The dissolution profile was obtained using a modification ofthe United States Pharmacopeia Apparatus I, at 37° C., 100 RPM, andwater as the dissolution media.

FIGS. 5 and 6 represent the in vivo profiles of propranololhydrochloride in two different human subjects dosed once a day with thecomposite capsule containing a total of 160 mg propranolol hydrochloride(FIG. 1) vs a total of 160 mg propranolol hydrochloride administered infour divided doses of 40 mg each. The individual components of thecomposite capsule are discernible as separate peaks in the plasma levelprofiles.

EXAMPLE 5

Vinpocetine hydrochloride (10.0 kg.) and microcrystalline cellulose(Avicel-PH-101); (80.0 kg.), citric acid monohydrate (10.0 kg) wereblended together in a 450 liter planetary mixer. Water (100 kg.) wasadded, and the mixer was run for 10 minutes until a homogeneous, plasticmass was obtained. The mass was extruded under pressure through aperforated cylinder to give cylindrical extrudates of nominally 1 mm.diameter.

The damp extrudates (in batches of 15 to 20 kg.) were placed in aspheronizer in which the rotating disc (diameter 68 cm.) rotated at 300to 400 r.p.m. The rotation was continued for 20 minutes, and theresulting spheroids were then dried at 80° C. in a fluidized bed drier.The dried spheroids were passed over a 1.2 mm. screen, and those whichpassed through were subjected to a 0.5 mm. screen. The over-andunder-sized spheroids were discarded.

The finished dosage form consists of a hard gelatin capsule containing apowder blend of vinpocetine and two types of spheroids. The formulationparticulars are based on 30 mg per capsule, although they can bedesigned to provide other dosage strengths.

The vinpocetine powder blend (or first group of spheroids) provides theloading dose, (e.g. 5 mg vinpocetine).

The second and third types of spheroids are categorized as:

(1) pH sensitive coated spheroids to provide a second dose (pH 6.5) e.g.12 mg vinpocetine.

(2) Coated spheroids to provide a third dose (4-10 hours post ingestion)e.g. 13 mg vinpocetine.

    ______________________________________                                                            Quantity                                                  ______________________________________                                        1.   Powder Blend                                                                  (a) Formula                                                              Ingredient                                                                    Vinpocetine           5        mg/capsule                                     Sodium Lauryl Sulfate, NF                                                                           0.1      mg/capsule                                     Sodium Starch Glycolate, NF                                                                         3        mg/capsule                                     Glutamic Acid, NF     6        mg/capsule                                     Starch, NF            7        mg/capsule                                     Lactose, USP          62       mg/capsule                                     Microcrystalline cellulose, NF                                                                      13       mg/capsule                                     Magnesium stearate, NF                                                                              1        mg/capsule                                     (b) Procedure                                                                 1. Blend the Vinpocetine, Lactose, Microcrystalline Cellulose,                Starch, Glutamic Acid, Sodium Starch Glycolate, Talc                          Triturate and the Sodium Lauryl Sulfate into the PK blender                   for 20 minutes with intensifier bar running.                                  2. Pass the Step #1 blend through a Fitz Mill using a #1B                     screen, medium speed, knives forward.                                         3. Return the granulation from Step #2 to the PK blender                      and add the Magnesium Stearate and blend for 2 minutes                        without the intensifier bar on.                                               2.   pH Sensitive Coated Spheroids                                            (i)  Eudragit S System:                                                            (a) Formula (based on 3 kg uncoated spheroids)                           Ingredients                                                                   Uncoated Spheroids (10%                                                                             3.00     28 kg                                          w/w Vinpocetine)                                                              Methacrylic Acid Copolymer,                                                                         0.75     kg                                             Type B, NF                                                                    Eudragit S                                                                    Triacetin, NF         0.112    kg                                             Methylene Chloride, NF                                                                              1.99     kg                                             Isopropyl Alcohol, NF 1.64     kg                                             Water, USP, Purified  0.50     kg                                             (b) Process                                                                   Uncoated spheroids were placed in a fluidized bed coater                      The Eudragit S solution was applied using a peristaltic pump                  The spheroids were dried                                                      3.   Coated Spheroids                                                              (a) Formula (based on 3 kg uncoated spheroids)                           Undercoat Ingredients                                                         Uncoated Spheroids (24%                                                                             3.00     kg                                             w/w vinpocetine                                                               Hydroxypropyl methylcellulose,                                                                      0.075    kg                                             USP, 2910, 4000 cps, (e.g.,                                                   Methocel E4MP)                                                                Methylene Chloride, NF                                                                              4.987    kg                                             Methanol, Anhydrous, NF                                                                             2.963    kg                                             Overcoat Ingredients                                                          Eudragit E 30 D (Aqueous                                                                            1.00     kg                                             Dispersion)                                                                   Calcium Stearate, NF  0.030    kg                                             Simethicone Emulsion, USP                                                                           0.0025   kg                                             Water, USP, Purified  0.500    kg                                             (b) Process for applying undercoat                                            The uncoated spheroids were placed in a fluidized bed coater                  Methocel E4MP solution was sprayed using a peristaltic pump                   The spheroids were dried                                                      (c) Process for applying overcoat                                             Eudragit E 30 D suspension containing calcium stearate was                    sprayed on the Methocel E4MP coated spheroids using a                         peristaltic pump                                                              The spheroids were dried                                                      4.   Manufacture                                                                   Capsules were filled with the powder blend, pH sensitive                      coated spheroids and coated spheroids on an encapsulating                     machine capable of dual filling powders and spheroids.                   ______________________________________                                    

EXAMPLE 6

The finished dosage form consists of a hard gelatin capsule containing 3types of spheroids. The formulation particulars are based on 30 mgvinpocetine per capsule, although they can be designed to provide otherdosage strengths.

The three types of spheroids are categorized as:

(1) Uncoated spheroids to provide a loading dose (e.g. 5 mg vinpocetine)

(2) pH sensitive coated spheroids to provide a second dose (pH 5.5) e.g.12 mg vinpocetine

(3) Coated spheroids to provide a third dose (4-10 hours post ingestion)e.g. 13 mg vinpocetine

    ______________________________________                                                              Quantity                                                ______________________________________                                        1.  Uncoated Spheroids                                                            prepared as described above in Example 5 except that                          5% of the microcrystalline cellulose was replaced                             with Avicel RC 581)                                                       2.  Alternate pH Sensitive Coated Spheroids                                       Polyvinyl Acetate Phthalate (PVAP) system:                                    (a) Formula - (based on 3 kg uncoated spheroids)                          Ingredients                                                                   Uncoated Spheroids (10% 3.00 kg                                               w/w vinpocetine HCl)                                                          Polyvinyl Acetate Phthalate (PVAP), NF                                                                0.30 kg                                               Triethyl Citrate, NF    0.03 kg                                               Stearic Acid, NF        0.06 kg                                               Methanol Anhydrous, NF  2.61 kg                                               (b) Process                                                                   Uncoated spheroids were placed in a fluidized bed coater                      The PVAP solution was applied using a peristaltic pump                        The spheroids were dried                                                      3.  Coated Spheroids (prepared as described above in Example 5)               Other dosage strengths of vinpocetine can be formulated                       as follows:                                                                             First group                                                                   of spheroids                                                                              Second group                                                                              Third group                                 Vinpocetine                                                                             (or powder) of spheroids                                                                              of spheroids                                mg per capsule                                                                          % of dose   % of dose   % of dose                                   ______________________________________                                        15 to 60  10% to 50%  20% to 75%  10% to 60%                                  ______________________________________                                    

EXAMPLE 7

Isosorbide dinitrate as a 50% triturate with lactose (60 kg) andmicrocrystalline cellulose (Avicel PH-101) (40 kg) are blended togetherin a 450 liter planetary mixer. Water (50 kg.) is added, and the mixeris run for 10 minutes until a homogeneous, plastic mass is obtained. Themass is extruded under pressure through a perforated cylinder to givecylindrical extrudates of nominally 1 mm. diameter.

The damp extrudates (in batches of 15 to 20 kg.) are placed in aspheronizer in which the rotating disc (diameter 68 cm.) rotates at 300to 400 r.p.m. The rotation is continued for 10 minutes, and theresulting spheroids are then dried at 60° C. in a fluidized bed drier.The dried spheroids are passed over a 1.4 mm. screen, and those whichpass through are subjected to a 0.7 mm. screen. The over-and under-sizedspheroids are discarded.

The finished dosage form consists of a hard gelatin capsule containing apowder blend of isosorbide dinitrate and two types of spheroids. Theformulation particulars are based on 40 mg per capsule, although theycan be designed to provide other dosage strengths.

The isosorbide dinitrate powder blend (or first group of spheroids)provides the loading dose, (e.g. 14 mg isosorbide dinitrate (100%).

The second and third types of spheroids are categorized as:

(1) pH sensitive coated spheroids to provide a second dose (pH 6.5) e.g.13 mg isosorbide dinitrate (100%).

(2) Coated spheroids to provide a third dose (4-10 hours post ingestion)e.g. 13 mg isosorbide dinitrate (100%).

    ______________________________________                                                            Quantity                                                  ______________________________________                                        1.   Powder Blend                                                                  (a) Formula                                                              Ingredient                                                                    Isosorbide dinitrate (100%) USP                                                                     5        mg/capsule                                     Lactose, USP          54       mg/capsule                                     Microcrystalline cellulose, NF                                                                      15       mg/capsule                                     Magnesium stearate, NF                                                                              1        mg/capsule                                     2.   pH Sensitive Coated Spheroids                                            (i)  Eudragit S System:                                                            (a) Formula (based on 3 kg uncoated spheroids)                           Ingredients                                                                   Uncoated Spheroids (30%                                                                             3.00     kg                                             w/w isosorbide dinitrate                                                      Methacrylic Acid Copolymer,                                                                         0.75     kg                                             Type B, NF                                                                    Eudragit S                                                                    Triacetin, NF         0.112    kg                                             Methylene Chloride, NF                                                                              1.99     kg                                             Isopropyl Alcohol, NF 1.64     kg                                             Water                 0.50     kg                                             (b) Process                                                                   Uncoated spheroids are placed in a fluidized bed coater                       The Eudragit S solution is applied using a peristaltic pump                   The spheroids are dried                                                       3.   Coated Spheroids                                                              (a) Formula (based on 3 kg uncoated spheroids)                           Undercoat Ingredients                                                         Uncoated Spheroids (30%                                                                             3.00     kg                                             w/w isosorbide dinitrate                                                      Hydroxypropyl methylcellulose,                                                                      0.075    kg                                             USP, 2910, 4000 cps,(e.g.,                                                    Methocel E4MP)                                                                Methylene Chloride, NF                                                                              4.987    kg                                             Methanol, Anhydrous, NF                                                                             2.963    kg                                             Overcoat Ingredients                                                          Eudragit E 30 D (Aqueous                                                                            1.00     kg                                             Dispersion)                                                                   Calcium Stearate, NF  0.030    kg                                             Simethicone Emulsion, USP                                                                           0.0025   kg                                             Water, USP, Purified  0.500    kg                                             (b) Process for applying undercoat                                            The uncoated spheroids are placed in a fluidized bed coater                   Methocel E4MP solution is sprayed using a peristaltic pump                    The spheroids were dried                                                      (c) Process for applying overcoat                                             Eudragit E 30 D suspension containing calcium stearate is                     sprayed on the Methocel E4MP coated spheroids using a                         peristaltic pump                                                              The spheroids are dried                                                       4.   Manufacture                                                                   Capsules are filled with a powder blend, pH sensitive                         coated spheroids and coated spheroids on an encapsulating                     machine capable of dual filling powders and spheroids.                   ______________________________________                                    

EXAMPLE 8

The finished dosage form consists of a hard gelatin capsule containing 3types of spheroids. The formulation particulars are based on 40 mgisosorbide dinitrate per capsule, although they can be designed toprovide other dosage strengths.

The three types of spheroids are categorized as:

(1) Uncoated spheroids to provide a loading dose (e.g. 14 mg isosorbidedinitrate)

(2) pH sensitive coated spheroids to provide a second dose (pH 5.5 e.g.13 mg isosorbide dinitrate

(3) Coated spheroids to provide a third dose (4-10 hours post ingestion)e.g. 13 mg isosorbide dinitrate

    ______________________________________                                                              Quantity                                                ______________________________________                                        1.  Uncoated Spheroids (prepared as described above)                          2.  Alternate pH Sensitive Coated Spheroids                                       Polyvinyl Acetate Phthalate (PVAP) system:                                    (a) Formula - (based on 3 kg uncoated spheroids)                          Ingredients                                                                   Uncoated Spheroids (30% 3.00 kg                                               w/w isosorbide dinitrate)                                                     Polyvinyl Acetate Phthalate (PVAP), NF                                                                0.30 kg                                               Triethyl Citrate, NF    0.03 kg                                               Stearic Acid            0.06 kg                                               Methanol, Anhydrous NF  2.61 kg                                               (b) Process                                                                   Uncoated spheroids are placed in a fluidized bed coater                       The PVAP solution is applied using a peristaltic pump                         The spheroids are dried                                                       3.  Coated Spheroids (prepared as described above in Example 7)               Other dosage strengths of isosorbide dinitrate can be                         formulated as follows:                                                                  First group                                                         Isosorbide                                                                              of spheroids                                                                              Second group                                                                              Third group                                 dinitrate (or powder) of spheroids                                                                              of spheroids                                mg per capsule                                                                          % of dose   % of dose   % of dose                                   ______________________________________                                        20 to 160 25% to 65%  25% to 65%  25% to 65%                                  ______________________________________                                    

EXAMPLE 9

Pelrinone, prepared as described in U.S. Pat. No. 4,505,910 (10 kg.) andmicrocrystalline cellulose (Avicel-PH-101; 90 kg.) are blended togetherin a 450 liter planetary mixer. Water (60 kg.) is added, and the mixeris run for 10 minutes until a homogeneous, plastic mass is obtained. Themass is extruded under pressure through a perforated cylinder to givecylindrical extrudates of nominally 1 mm. diameter.

The damp extrudates (in batches of 15 to 20 kg.) are placed in aspheronizer in which the rotating disc (diameter 68 cm.) rotates at 300to 400 r.p.m. The rotation is continued for 10 minutes, and theresulting spheroids are then dried at 60° C. in a fluidized bed drier.The dried spheroids are passed over a 1.4 mm. screen, and those whichpass through are subjected to a 0.7 mm. screen. The over-and under-sizedspheroids are discarded.

The finished dosage form consists of a hard gelatin capsule containing apowder blend of pelrinone and two types of spheroids. The formulationparticulars are based on 15 mg pelrinone per capsule, although they canbe designed to provide other dosage strengths.

The pelrinone powder blend (or first group of spheroids) provides theloading dose, (e.g. 3 mg pelrinone).

The second and third types of spheroids are categorized as:

(1) pH sensitive coated spheroids to provide a second dose (pH 6.5) e.g.6 mg pelrinone.

(2) Coated spheroids to provide a third dose (4-10 hours post ingestion)e.g. 6 mg pelrinone.

    ______________________________________                                                           Quantity                                                   ______________________________________                                        1.   Powder Blend                                                                  (a) Formula                                                              Ingredient                                                                    Pelrinone            3        mg/capsule                                      Lactose, USP         54       mg/capsule                                      Microcrystalline cellulose, NF                                                                     15       mg/capsule                                      Magnesium stearate, NF                                                                             1        mg/capsule                                      2.   pH Sensitive Coated Spheroids                                            (i)  Eudragit S System:                                                            (a) Formula (based on 3 kg uncoated spheroids)                           Ingredients                                                                   Uncoated Spheroids (60%                                                                            3.00     kg                                              w/w pelrinone)                                                                Methacrylic Acid Copolymer,                                                                        0.75     kg                                              Type B, NF                                                                    Eudragit S                                                                    Triacetin, NF        0.112    kg                                              Methylene Chloride, NF                                                                             1.99     kg                                              Isopropyl Alcohol, NF                                                                              1.64     kg                                              Water                0.50     kg                                              (b) Process                                                                   Uncoated spheroids are placed in a fluidized bed coater                       The Eudragit S solution is applied using a peristaltic pump                   The spheroids are dried                                                       3.   Coated Spheroids                                                              (a) Formula (based on 3 kg uncoated spheroids)                           Undercoat Ingredients                                                         Uncoated Spheroids (60%                                                                            3.00     kg                                              w/w pelrinone                                                                 Hydroxypropyl methylcellulose,                                                                     0.075    kg                                              USP, 2910, 4000 cps, (e.g.,                                                   Methocel E4MP)                                                                Methylene Chloride, NF                                                                             4.987    kg                                              Methanol, Anhydrous, NF                                                                            2.963    kg                                              Overcoat Ingredients                                                          Eudragit E 30 D (Aqueous                                                                           1.00     kg                                              Dispersion)                                                                   Calcium Stearate, NF 0.030    kg                                              Simethicone Emulsion, USP                                                                          0.0025   kg                                              Water                0.500    kg                                              (b) Process for applying undercoat                                            The uncoated spheroids are placed in a fluidized bed coater                   Methocel E4MP solution is sprayed using a peristaltic pump                    The spheroids are dried                                                       (c) Process for applying overcoat                                             Eudragit E 30 D suspension containing calcium stearate is                     sprayed on the Methocel E4MP coated spheroids using a                         peristaltic pump                                                              The spheroids are dried                                                       4.  Manufacture                                                                   Capsules are filled with the powder blend, pH sensitive                       coated spheroids and coated spheroids on an encapsulating                     machine capable of dual filling powders and spheroids.                    ______________________________________                                    

EXAMPLE 10

The finished dosage form consists of a hard gelatin capsule containing 3types of spheroids. The formulation particulars are based on 15 mgpelrinone per capsule, although they can be designed to provide otherdosage strengths.

The three types of spheroids are categorized as:

(1) Uncoated spheroids to provide a loading dose (e.g. 3 mg pelrinone)

(2) pH sensitive coated spheroids to provide a second dose (pH 5.5) e.g.6 mg pelrinone

(3) Coated spheroids to provide a third dose (4-10 hours post ingestion)e.g. 6 mg pelrinone

    ______________________________________                                                              Quantity                                                ______________________________________                                        1.  Uncoated Spheroids (prepared as described above                           2.  Alternate pH Sensitive Coated Spheroids                                       Polyvinyl Acetate Phthalate (PVAP) system:                                    (a) Formula - (based on 3 kg uncoated spheroids)                          Ingredients                                                                   Uncoated Spheroids (10% 3.00 kg                                               w/w pelrinone)                                                                Polyvinyl Acetate Phthalate (PVAP), NF                                                                0.30 kg                                               Triethyl Citrate, NF    0.03 kg                                               Stearic Acid, NF        0.06 kg                                               Methanol, Anhydrous, NF 2.61 kg                                               (b) Process                                                                   Uncoated spheroids are placed in a fluidized bed coater                       The PVAP solution is applied using a peristaltic pump                         The spheroids are dried                                                       3.  Coated Spheroids (prepared as described above in Example 1)               Other dosage strengths of pelrinone can be formulated                         as follow:                                                                              First group                                                                   of spheroids                                                                              Second group                                                                              Third group                                 pelrinone (or powder) of spheroids                                                                              of spheroids                                mg per capsule                                                                          % of dose   % of dose   % of dose                                   ______________________________________                                        5 to 50   10% to 50%  20% to 75%  10% to 60%                                  ______________________________________                                    

We claim:
 1. A therapeutic composition for once daily oral administration consisting essentially of a pharmaceutical gelatin capsule containing a powder blend of isosorbide dinitrate and two groups of coated spheroids each also containing isosorbide dinitrate wherein,(a) said powder blend comprises 10% to 50% by weight of isosorbide dinitrate in admixture with pharmaceutical excipients for immediate release of isosorbide dinitrate to provide a loading dose of isosorbide dinitrate, (b) said first group of spheroids comprises film coated spheroids, which spheroids prior to coating comprise 20% to 75% by weight of isosorbide dinitrate in admixture with non-water swellable cellulose, said film coating comprising (i) a copolymer based on methacrylic acid and methacrylic acid methyl ester or (ii) polyvinyl acetate phthalate, said first group of film coated spheroids having a pH sensitive coating to provide a delayed second dose of isosorbide dinitrate and (c) said second group of spheroids comprises film coated spheroids, which spheroids prior to coating comprise 10% to 60% by weight of isosorbide dinitrate in admixture with non-water swellable microcrystalline cellulose, and said film coating comprising (i) an undercoat selected from the group consisting of hydroxypropyl methylcellulose and hydroxypropyl methylcellulose containing as a disintegrant carboxymethylcellulose sodium or sodium starch glycolate and (ii) an overcoat consisting of a neutral copolymer based on polymethacrylic acid esters containing metallic stearates, said second group of film coated spheroids being double coated with an effective thickness to provide a further delayed third dose of isosorbide dinitrate.
 2. A therapeutic composition for once daily oral administration consisting essentially of a pharmaceutical gelatin capsule containing three groups of spheroids each containing isosorbide dinitrate wherein(a) said first group of spheroids comprises 10% to 50% by weight of isosorbide dinitrate in admixture with non-water swellable microcrystalline cellulose for immediate release of isosorbide dinitrate to provide a loading dose of isosorbide dinitrate (b) said second group of spheroids comprises film coated spheroids, which spheroids prior to coating comprise 10% to 60% by weight of isosorbide dinitrate in admixture with non-water swellable cellulose, said film coating comprising (i) a copolymer based on methacrylic acid and methacryclic acid methyl ester or (ii) polyvinyl acetate phthalate, said first group of film coated spheroids having a pH sensitive coating to provide a delayed second dose of isosorbide dinitrate, and (c) said third group of spheroids comprises film coated spheroids, which spheroids prior to coating comprise 40% to 65% by weight of isosorbide dinitrate in admixture with non-water swellable microcrystalline cellulose and said film coating comprising (i) an undercoat selected from the group consisting of hydroxypropyl methylcellulose and hydroxypropyl methylcellulose containing as a disintegrant carboxymethylcellulose sodium or sodium starch glycolate and (ii) an overcoat consisting of a neutral copolymer based on polymethacrylic acid esters containing metallic stearates, said second group of film coated spheroids being double coated with an effective thickness to provide a further delayed third dose of isosorbide dinitrate.
 3. A therapeutic composition according to claims 1 or 2 wherein said gelatin capsule contains a total of from 20 mg to 160 mg isosorbide dinitrate, wherein(a) said first group of spheroids or powder blend contains 25% to 65% of the total dose of isosorbide dinitrate, (b) said second group of spheroids contains 25% to 65% of the total dose of isosorbide dinitrate and said spheroids are coated with a copolymer based on methacrylic acid and methacrylic acid methyl ester and triacetin, and (c) said third group of spheroids contains 25% to 65% of the total dose of isosorbide dinitrate and said spheroids are coated with an undercoat of hydroxypropyl methylcellulose and an overcoat of a copolymer based on polymethacrylic acid esters.
 4. A therapeutic composition according to claim 3 wherein said gelatin capsule contains a total of 30 mg isosorbide dinitrate, wherein(a) said first group of spheroids contains 25% to 65% of the total dose of isosorbide dinitrate, (b) said second group of spheroids contains 25% to 65% of the total dose of isosorbide dinitrate and said spheroids are coated with the copolymer based on methacrylic acid and methacrylic acid methyl ester and triacetin, and (c) said third group of spheroids contains 25% to 65% of the total dose of isosorbide dinitrate and said spheroids are coated with an undercoat of hydroxypropyl methylcellulose and an overcoat of a copolymer based on polymethacrylic acid esters.
 5. A therapeutic composition for oral administration consisting essentially of a pharmaceutical gelatin capsule containing film coated spheroids, which spheroids prior to coating comprise 10% to 60% by weight of an isosorbide dinitrate in admixture with non-water swellable microcrystalline cellulose, and said film coating comprising (i) an undercoat selected from the group consisting of hydroxypropyl methylcellulose and hydroxypropyl methylcellulose containing as a disintegrant carboxymethylcellulose sodium or sodium starch glycolate and (ii) an overcoat consisting of a copolymer based on polymethacrylic acid esters containing metalic stearates. 